chr1-42930865-G-A

Variant names:

• chr1-42930865-G-A
• rs267607061
• NM_006516.4:c.277C>T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_006516.4(SLC2A1):​c.277C>T​(p.Arg93Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000125 in 1,600,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R93Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SLC2A1 NM_006516.4 missense, splice_region
• Scores: Splicing: ADA: 0.9721
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 2.92
• Publications: 10 publications found

Genes affected

SLC2A1 (HGNC:11005): (solute carrier family 2 member 1) This gene encodes a major glucose transporter in the mammalian blood-brain barrier. The encoded protein is found primarily in the cell membrane and on the cell surface, where it can also function as a receptor for human T-cell leukemia virus (HTLV) I and II. Mutations in this gene have been found in a family with paroxysmal exertion-induced dyskinesia. [provided by RefSeq, Apr 2013]

SLC2A1 Gene-Disease associations (from GenCC):

• encephalopathy due to GLUT1 deficiency

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• GLUT1 deficiency syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• childhood onset GLUT1 deficiency syndrome 2

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• dystonia 9

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• epilepsy, idiopathic generalized, susceptibility to, 12

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• childhood absence epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary cryohydrocytosis with reduced stomatin

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• myoclonic-astatic epilepsy

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_006516.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-42930864-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 623684.
• PP2: Missense variant in the SLC2A1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 98 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: 2.9256 (below the threshold of 3.09). Trascript score misZ: 4.6729 (above the threshold of 3.09). GenCC associations: The gene is linked to epilepsy, idiopathic generalized, susceptibility to, 12, GLUT1 deficiency syndrome, encephalopathy due to GLUT1 deficiency, dystonia 9, hereditary cryohydrocytosis with reduced stomatin, childhood onset GLUT1 deficiency syndrome 2, childhood absence epilepsy, myoclonic-astatic epilepsy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944
• PP5: Variant 1-42930865-G-A is Pathogenic according to our data. Variant chr1-42930865-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 16117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006516.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC2A1	NM_006516.4	MANE Select	c.277C>T	p.Arg93Trp	missense splice_region	Exon 4 of 10	NP_006507.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC2A1	ENST00000426263.10	TSL:1 MANE Select	c.277C>T	p.Arg93Trp	missense splice_region	Exon 4 of 10	ENSP00000416293.2
	SLC2A1	ENST00000674765.1		c.277C>T	p.Arg93Trp	missense splice_region	Exon 4 of 9	ENSP00000501811.1
	SLC2A1	ENST00000475162.3	TSL:5	c.175C>T	p.Arg59Trp	missense splice_region	Exon 3 of 4	ENSP00000487213.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1448682 Hom.: 0 Cov.: 33 AF XY: 0.00000139 AC XY: 1 AN XY: 721034

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111924

Other (OTH) AF: 0.00 AC: 0 AN: 60312

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152118 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74298

African (AFR) AF: 0.00 AC: 0 AN: 41410

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000396 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 14, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported previously in a mother and her two children with variable features ranging from mild to severe intellectual disability, ataxia, chorea, and/or seizures (PMID: 20129935); Published functional studies suggest that this variant is associated with reduced glucose uptake (PMID: 18387950); This variant is associated with the following publications: (PMID: 18403583, 29303961, 31302675, 23448551, 23106342, 24847886, 24824604, 26986070, 21445818, 33163569, 31440721, 36054588, 20129935, 18387950, 19996082)

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Encephalopathy due to GLUT1 deficiency Pathogenic:2

Sep 10, 2019

New York Genome Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant c.277C>T, p.Arg93Trp has been reported in multiple individuals with GLUT1 deficiency syndrome [MIM#606777] [PMID: 24847886; PMID: 2344855; PMID:23106342; PMID: 19996082]. This mutation is located in the first cytosolic loop of the protein [PMID: 19996082]. The variant has 0.003% allele frequency in the gnomAD database (1 out of 31,368 heterozygous alleles) indicating this is a rare variant and in silico tool predicts the variant is expected to be deleterious. Functional studies suggest that the variant results in reduced glucose uptake [PMID: 18387950]. Based on the available evidence, the variant c.277C>T, p.Arg93Trp in the SLC2A1 gene is classified as pathogenic.

Apr 11, 2023

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Childhood onset GLUT1 deficiency syndrome 2 Pathogenic:2

Dec 08, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Mar 19, 2025

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.74 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.99 (> 0.75, sensitivity 0.96 and precision 0.92)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000016117 / PMID: 19996082). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 19996082). A different missense change at the same codon (p.Arg93Gln) has been reported to be associated with SLC2A1-related disorder (ClinVar ID: VCV000623684 / PMID: 22190371). However the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

SLC2A1-related disorder Pathogenic:1

Aug 18, 2022

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SLC2A1 c.277C>T variant is predicted to result in the amino acid substitution p.Arg93Trp. This variant has been reported in multiple individuals with GLUT1 deficiency (Joshi et al. 2008. PubMed ID: 18403583; Arsov et al. 2012. PubMed ID: 23106342; Ramm-Pettersen et al. 2013. PubMed ID: 23448551; Supplemental Table for Symonds et al. 2019. PubMed ID: 31302675) and an individual with alternating hemiplegia of childhood (Rotstein et al, 2009. PubMed ID: 19996082). An alternate substitution of the same amino acid has also been reported in association with GLUT1 deficiency (Magrinelli et al. 2020. PubMed ID: 32753446). In a functional study, the p.Arg93Trp substitution was reported to reduce glucose transport in erythrocytes (Pascual et al. 2008. PubMed ID: 18387950) This variant is reported in 0.029% of alleles in individuals of European (Finnish) descent in gnomAD (1 of 31,368 total alleles in http://gnomad.broadinstitute.org/variant/1-43396536-G-A). This variant is interpreted as pathogenic or likely pathogenic by multiple independent submitters to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/16117). Based on the collective evidence, this variant is interpreted as pathogenic.

GLUT1 deficiency syndrome 1, autosomal recessive Pathogenic:1

Nov 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 93 of the SLC2A1 protein (p.Arg93Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with low cerebral spinal fluid blood glucose concentrations, findings that are highly specific for GLUT1 deficiency syndrome (PMID: 18403583, 19996082, 20129935, 23106342, 23448551). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16117). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic.

GLUT1 deficiency syndrome Pathogenic:1

Jan 15, 2025

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD <0.001 for a dominant condition (v4: 2 heterozygote(s), 0 homozygote(s)) ; This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic or likely pathogenic by multiple clinical laboratories and reported in the literature in individuals with GLUT1 deficiency/alternating hemiplegia of childhood (PMIDs: 23448551, 19996082); Missense variant predicted to be damaging by in silico tool(s) or highly conserved with a major amino acid change; This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). Additional information: Variant is predicted to result in a missense amino acid change from arginine to tryptophan; This variant is heterozygous; This gene is associated with autosomal dominant disease. Most individuals have autosomal dominant disease; however, rare cases have been described with an autosomal recessive mode of inheritance (PMID: 31196579); Variant is located in the annotated sugar (and other) transporter domain (DECIPHER); Loss of function is a known mechanism of disease in this gene and is associated with SLC2A1-related disease (OMIM); The condition associated with this gene has incomplete penetrance. Incomplete penetrance has been reported in families with GLUT1 deficiency syndrome or epilepsy, who were heterozygous for pathogenic missense variants (OMIM, PMID: 18451999); Variants in this gene are known to have variable expressivity (PMID: 20129935).

Seizure Pathogenic:1

Aug 03, 2021

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		2.9
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.75		Gain of catalytic residue at M96 (P = 0.0048)
MVP		0.95
MPC		2.1
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.86
gMVP		0.87
Mutation Taster		=9/91	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Benign	0.68
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs267607061; hg19: chr1-43396536;